(Trends Wide) — In the fall of 2015, Dr. Mark Denison was preparing for a long drive home from Alabama after giving a presentation at a scientific meeting when a colleague asked him to stay for lunch and check out some facts about a possible new drug. .
Denison said yes, and six years later, he’s very glad he stayed.
Denison’s colleague George Painter is a “drug hunter” at Emory University in Atlanta. At lunch, he showed Denison the lab results he had obtained with a new antiviral compound, now known as molnupiravir.
“It just blew me away,” said Denison, an infectious disease specialist at Vanderbilt University Medical Center. “With increasing concentrations of the drug, the virus’s ability to grow just plummeted.”
Painter’s lab analyzed the effect molnupiravir had against influenza viruses and chikungunya, a virus that is transmitted by mosquitoes. After the Alabama meeting, Painter sent some of the compound to Denison, who tested it in his lab against the virus that causes Middle East Respiratory Syndrome.
“We were surprised at how effective it was,” recalls Denison.
At the time, neither Painter nor Denison, nor anyone else, knew that another significant potential application of molnupiravir was looming in the real world.
It is to fight SARS-CoV-2, the virus that causes covid-19.
Merck and Ridgeback Pharmaceuticals now own molnupiravir, and on November 30, a team of infectious disease advisers from the U.S. Food and Drug Administration (FDA) will review the results of its clinical trial. and will decide whether to recommend emergency use authorization for the early treatment of COVID-19 with the drug.
The results, which have not yet been reviewed by the FDA or published in a medical journal, are quite surprising: The pill reduced hospitalizations and deaths by about 50%, according to a Merck news release in October.
“I wanted to scream from the rooftops about molnupiravir, so this is like sending our baby to college,” Denison said.
But it is not clear what kind of grades that baby will receive.
Molnupiravir works in an unusual way and there is concern that it may be dangerous to developing fetuses. The company’s clinical trials did not include pregnant women, and Daria Hazuda, who leads research on Merck’s molnupiravir, says the FDA could limit its use in pregnant women.
There is also concern that the pill could lead to the development of vaccine-resistant new coronavirus mutations. Hazuda said Merck’s research shows that the drug does not lead to such strains.
At the end of the day, the FDA and its advisers will have to use the available data to weigh whether the drug is worth the potential risks.
“We have to worry about the dangers to pregnant women and the dangers of developing resistance. But if we have a drug that works, we want that drug. We just have to figure out the best way to use it given its limitations,” said Dr. Eric Rubin, infectious disease expert at Harvard’s TH Chan School of Public Health and editor-in-chief of the New England Journal of Medicine.
“Remarkable” results in COVID-19 trials
Doctors don’t have much to offer patients in the early stages of COVID-19.
There is an FDA-cleared treatment for early covid, but monoclonal antibodies involve injections or an infusion and are often difficult for patients to access.
However, molnupiravir is a pill, and a doctor can easily prescribe it, pick it up at the pharmacy, and take it at home. That is why it is important for the FDA to authorize the drug.
Regulatory authorities in the UK approved the drug on November 4.
Another antiviral pill is also being prepared. Merck applied to the FDA for authorization of molnupiravir on October 11, and last week, Pfizer applied for authorization for its antiviral pill for COVID-19. The FDA has not yet set a date for its advisory panel to review the Pfizer drug.
In the Merck and Pfizer clinical trials, participants took the drug within days of feeling COVID-19 symptoms.
The drugs appear to be very effective, based on clinical trial data provided by Merck and Pfizer. In fact, they worked so well that in both cases, an independent clinical trial oversight board suggested that the trials be stopped so that the companies could go ahead with the application to the FDA.
In Merck’s clinical trial, about half of the 762 participants received molnupiravir and the other half received a placebo, a pill that does nothing, and neither the patients nor their doctors knew who was receiving which.
About a month passed and 45 participants who received the placebo were hospitalized and nine of them died. Among the group that received the drug, 28 were hospitalized and none died.
“For me, the game changer is 9 and 0. That’s pretty impressive,” said Dr. Peter Hotez, an infectious disease specialist at Baylor School of Medicine.
“Those results are dramatic. They are not subtle,” added Rubin, the Harvard infectious disease expert.
Merck’s Molnupiravir “Coding for Catastrophes”
When scientists Brandon Malone and Elizabeth Campbell wrote about Merck’s antiviral drug, they titled their article Molnupiravir: coding for catastrophes.
They said it as a compliment.
The drug works by wreaking havoc with the way the covid-19 virus copies itself. The virus is an RNA virus, which means that its genetic material is stored in RNA, not DNA. RNA has four protein bases, called A, C, G, and U. When the virus replicates, C always pairs with G and A always pairs with U.
Anything that interferes with those pairings will stop the virus in its tracks, and that’s what molnupiravir is designed for.
The drug is disguised as a base that looks like C, but it doesn’t always act like the real C, so it is sometimes paired with A instead of G.
“The false C becomes promiscuous and pairs with the wrong partner, and now the genome is not what it is supposed to be, and the virus will be depleted and die,” said Campbell, an associate professor of research at Rockefeller University.
This mechanism is called “lethal mutagenesis,” Campbell and his co-author wrote in their September paper in Nature Structural and Molecular Biology.
Some other antiviral drugs have used this mechanism, or something similar, and there has been a theoretical concern about “off-target effects”: While the drug is intended to interfere with only the genetic material of the virus, what if, Inadvertently, it also interferes with human genetic material?
“Possible off-target effects will require further investigation,” Campbell and his colleague concluded in their Nature paper.
A Cal Tech scientist was much more forthright in his letter to the FDA earlier this month.
“Every deliberation and decision of this Advisory Committee and the FDA is consequential. However, given the potential impact on the world, this decision, whether molnupiravir is authorized and under what conditions, may be among the [decisiones] most important of all, “wrote Rustem Ismagilov, a professor of Chemistry and Chemical Engineering at the California Institute of Technology, who has conducted research on COVID-19.
In an interview with Trends Wide, Hazuda, vice president of Infectious Disease Discovery at Merck, addressed concerns that molnupiravir could lead to vaccine-resistant mutations and that the drug could be harmful to a developing fetus.
Once people become infected with COVID-19, the virus mutates within the infected person. Hazuda said the mutations were no more common among clinical trial participants taking molnupiravir than among those taking a placebo. And for all the participants, he said, the mutations weren’t new.
“Each of the mutations are mutations that have been previously observed and are currently circulating,” said Hazuda, a virologist.
As for possible harm to a developing fetus, Hazuda said the FDA may be able to limit the use of the drug in pregnant women.
“The precise language to be included on the label has yet to be determined and is still in negotiations with the agency,” Hazuda said.
Hotez, Baylor’s infectious disease expert, notes that there is no reason to think that molnupiravir would interfere with human genetics.
“It’s more of a theoretical concern, but it’s something to keep in mind,” Hotez said. “I think I would be concerned about taking this drug if I was pregnant.”
“If I were pregnant, I wouldn’t take it,” added Campbell, Rockefeller’s microbial biochemist. “I assume that the FDA will not allow molnupiravir to be used in pregnant women.”
These concerns are likely to be a big point of discussion when the FDA’s Antimicrobial Drug Advisory Committee meets Nov. 30 to consider Merck’s application for emergency use.
If the committee approves the drug, with or without limitations on who can get it, the FDA itself will issue a decision, which could happen in a few days.
“Having an antiviral is a good thing. It’s just good. We really have to be on the lookout for issues like mutagenesis, we have to be on the lookout for resistance and see if there are strategies to lower that risk,” said Rubin, the infectious disease specialist at Harvard. “But wow, it would be great to have something, if the Merck data is correct, to reduce the risk of hospitalizations and death by 50%. That’s amazing.”
A long road for molnupiravir
Whatever the final FDA decision, it has been a long road for molnupiravir.
Painter, the Emory scientist credited with discovering molnupiravir, began studying it in 2013, selecting it from among many other potential compounds he analyzes each year.
“I think of George Painter as a drug hunter, and I don’t think people realize it, but he’s an incredibly rare breed,” said Todd Sherer, Associate Vice President for Research in Emory’s Office of Technology Transfer. “Only one in 10,000 new molecules will hit the market.”
Painter declined to be interviewed for this story.
The development of molnupiravir, which was originally known as EIDD-2801, was funded with resources from the National Institute of Allergy and Infectious Diseases and the Defense Threat Reduction Agency, according to Emory.
In January 2020, Painter met with Wendy Holman, CEO of Ridgeback Biotherapeutics, at a scientific conference. Emory and Ridgeback teamed up, first considering molnupiravir to treat Ebola, but then reversing course when the COVID-19 pandemic took off in the following months, according to Davidson Goldin, a Ridgeback spokesman.
If molnupiravir hits the market, it will be a first for Painter’s group, Drug Innovation Ventures at Emory, which was established in 2012.
Denison, the Vanderbilt professor and one of Painter’s early collaborators, remembers the day six years ago when he first heard about the drug over lunch in Birmingham, Alabama.
“Some things in life are just transformative,” he said.
Trends Wide’s Danielle Herman, Justin Lape and Nadia Kounang contributed to this report.